Molecular dynamics simulation provides a possible structure for substance P‐like peptides in aqueous solution

Abstract

A hypothetical conformation of the undecapeptide Substance P in aqueous solution is generated by molecular dynamics simulation for 284 ps. The conformation takes explicit solvent interactions into account as well as entropic effects to the extent that phase space is sampled in simulation. The initial conformation is taken from energy minimization studies and modified. In spite of fluctuations through 180 degrees in some backbone dihedral angles, the peptide settles with all backbone dihedrals within +/- 60 degrees from the initial values. In 130 ps, the radius of gyration decreases from 6.2 A to 5.5 A, whereas only fluctuation (+/- .2 A) is observed during the last 150 ps. The root-mean-square deviation at optimal superposition for a pair of conformations from the last 150 ps is 0.6 A, based on backbone atoms. The final structure is close-knit, nearly globular, and stabilized by several long-lived hydrogen bonds. The simulation conformation agrees with the scarce experimental data including a large number of structure-activity relationships. Thus, the simulation conformation is a likely candidate for one of the several conformations, the existence of which has been deduced from nuclear magnetic resonance data. Simulation results and experimental modification studies suggest that Phe 8 and Leu 10 are involved in the primary binding of SP to its receptors.

Molecular dynamics simulation of the renin inhibitor H142 in water

“…The diffusion coefficient, which is meaningful only in the aqueous simulations, was found to be 4.6 x 10-10 m2/s (H 142) and 3.1 x 10-10 m2/s (H 142n). The values are similar to the one obtained for Substance P [35].…”

“…For H142, we believe that some folding will occur, so that the reorientation of the present elongated conformation is not the same as for the peptide at equilibrium. The H 142 rotation is slower than that of Substance P, a peptide of similar size, which assumed a folded conformation in a simulation by Teleman and v. d. Lieth [35].…”

“…The same applies to the.side chains containing such atoms, His 2, His 5, His 9 and Lys 1°. The opposite situation occurred in the simulation of an 11-residue peptide in a folded state (Substance P, [35]), where 307 hydrogen bonds longer-lived than 1 ps were found.…”

260 ps Molecular Dynamics Simulation of Substance P With Hydrated Dimyristoyl Phosphatidyl Choline Bilayer

“…It has been now established that 3D structure of a peptide is directly related to its biological activity (25). The most important conformational feature that distinguishes them from other biological active chemical compounds is the level of their conformational flexibility in physiological environment.…”

CD,1H NMR and molecular modeling studies of the interaction of Ca2+ with substance P and Ala7-substance P in a non-polar solvent

“…A great deal of effort has, therefore, been put into the detailed structural analysis of SP. The hormone exists as an ensemble of flexible structures in water [8][9][10][11][12][13], although there is some evidence that some degree of hydrogen-bonded ordered structure may also be present [13]. It has been suggested that the lipid milieu in which most peptide hormones would interact with membrane-bound receptors may impose specific constraints on hormone structure [3,14,15], so that the structure determined in lipid bilayers or micelles is generally regarded as a closer approximation to the bioactive conformation of SP than the structure prevailing in water.…”